The long-term goals of this proposal are to characterize DISC-1 (Disrupted ln-Schizophrenia) and its interacting proteins and determine their roles in the pathogenesis of major mental illnesses including schizophrenia (SZ). In one large family with hereditary SZ, a balanced translocation in the DISC-1 gene segregates with major psychiatric illnesses with a LOD score of 7.1. The translocation leads to a truncation of the DISC-1 protein product. Thus, DISC-1 appears be the first causative gene mutation identified for SZ and related psychiatric conditions. Research in Alzheimer's and Parkinson's diseases has been greatly advanced by the understanding of rare familial cases, involving causative mutations in gene products such as presenilin, and alpha-synuclein. We propose to use a similar strategy for SZ, by focusing on DISC-l. While DISC-1 mutations may be very rare, the biology of DISC-1 and its protein interaction partners will help elucidate the pathogenesis of major mental disorders in the Scottish family and likely in some other familial, and possibly sporadic, cases as well. Our preliminary results suggest that DISC-1 and its interactors play a role in neurodevelopment and can be linked to cortical developmental disorders. Therefore our overall hypothesis is that cascades that include DISC-1 and its interactors may have important functions in cell structure and cell signaling during neural development. Aim 1 will screen DISC-1 protein interactors and characterize their binding by yeast two-hybrid (Y2H) assays. In Aim 2, the putative protein interactions will be confirmed and characterized by biochemical and molecular cell approaches. Aim 3 will provide functional analyses of DISC-1 and its interators in cell and animal models by modulating expression of these proteins by transfection of expression and RNAi constructs and examining the effects on cell structure and signaling, especially neurite outgrowth and neuronal migration. In Aim 4 autopsied brain samples from controls and patients with major mental illnesses such as SZ will be analyzed for changes in DISC-1 and its interactors. Together these studies will clarify the molecular and cellular functions of DISC-1 and its protein interaction partners. They will provide information to understand the pathogenesis of major mental illnesses in the Scottish family, and they may provide insight into some of the mechanisms that underlie SZ and major mental illnesses.